4.7 Article

Antitumor Effect of Hyperoside Loaded in Charge Reversed and Mitochondria-Targeted Liposomes

期刊

INTERNATIONAL JOURNAL OF NANOMEDICINE
卷 16, 期 -, 页码 3073-3089

出版社

DOVE MEDICAL PRESS LTD
DOI: 10.2147/IJN.S297716

关键词

mitochondria-targeted; liposome; charge reversal; antitumor; hyperoside

资金

  1. National Natural Science Foundation of China [81703944]
  2. Heilongjiang Natural Science Foundation Project [YQ2019H031]
  3. Post-doctoral Researchers Settled in Heilongjiang Scientific Research Startup Fund
  4. Outstanding Innovative Talents Project from Heilongjiang University of Chinese medicine

向作者/读者索取更多资源

The novel dual-functional liposome system possessing both extracellular charge reversal and mitochondrial targeting properties significantly enhances drug accumulation in mitochondria and triggers apoptosis of cancer cells. The results demonstrate that the charge reversed and mitochondria-targeted liposomes facilitate cellular internalization and mitochondrial accumulation for enhanced antitumor effect. Therefore, this liposome system represents a promising anticancer drug delivery system for improved therapeutic efficacy.
Introduction: Hyperoside (HYP), a flavonol glycoside compound, has been shown to significantly inhibit the proliferation of malignant tumors. Mitochondria serve as both energy factories and suicide weapon stores of cells. Targeted delivery of cytotoxic drugs to the mitochondria of tumor cells and tumor vascular cells is a promising strategy to improve the efficacy of chemotherapy. Objective: We report a novel dual-functional liposome system possessing both extracellular charge reversal and mitochondrial targeting properties to enhance drug accumulation in mitochondria and trigger apoptosis of cancer cells. Methods: L-lysine was used as a linker to connect 2,3-dimethylmaleic anhydride (DMA) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) to yield a new compound, DSPE-Lys-DMA (DLD). Then, DLD was mixed with other commercially available lipids to form charge reversed and mitochondria-targeted liposomes (DLD-Lip). The size, morphology, zeta potential, serum stability, and protein adsorption of the HYP loaded DLD-Lip (HYP/DLD-Lip) were measured. The release profile, cellular uptake, in vitro and in vivo toxicity, and anticancer activity of HYP/DLD-Lip were investigated. Results: The results showed that the mean diameter of the liposomes was less than 200 nm. The zeta potential of the liposomes was negative at pH 7.4. However, the zeta potential was positive at weak acidic pH values with the cleavage of the DMA amide. The charge reversion of HYP/DLD-Lip facilitated the cellular internalization and mitochondrial accumulation for enhanced antitumor effect. The strongest tumor growth inhibition (TGI 88.79%) without systemic toxicity was observed in DLD/HYP-Lips-treated CBRH-7919 tumor xenograft BALB/C mice. Conclusion: The charge reversed and mitochondria-targeted liposomes represented a promising anticancer drug delivery system for enhanced anticancer therapeutic efficacy.

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